Although the 'reverse genetics'approach has associated SLE disease risk with several genes with known immune function including complement proteins, antibody receptors and immune signaling molecules, the newly developed ability to scan the entire genome provides an unprecedented opportunity for novel discovery of critical pathways in disease pathogenesis. SLEGEN, a productive multi-institutional consortium of lupus investigators, matches the capacity for current state-of-the-art genome-wide technology with large phenotypically characterized participant collections which provide appropriate statistical power for genomewide studies. SLEGEN has successfully conducted a genome wide association study (GWAS) with independent replication in European-derived populations and has both confirmed previous candidate genes and discovered multiple new genetic effects. As a result of SLEGEN, and the work of others, the genetic variants known to contribute to the risk of lupus now include ITGAM (CDI lb, CR3), STAT4, BANKl, BLK, HLA-DR, IRF5, FCGR3A, FCGR2A, Clq, Complement C4, and PTPN22, among others. However, both the phenotypic variation in other populations with different ancestries and initial data indicate that not all European variants have similar roles in these populations and that we have much to learn about the genetic architecture of human lupus. A trans-racial mapping approach provides a unique opportunity to identify both variants in common and variants which may be population specific. SLEGEN is uniquely positioned to take advantage of this opportunity. Project 1 will explore the HLA region variation in >6000 subjects who are African-American, Amerindian admixed Hispanics, or Asians and grounded at HLA-DRB2 using existing genome data for European-derived subjects. Projects 2-4 will explore the whole genome by evaluating 1.8 million markers in 6000 non-European subjects with replication, fine mapping, and trans-racial mapping in 9000 additional subjects. This will be the largest genomic exploration attempted in lupus, and in aggregate, will benefit from genetic data assembled from >27,000 cases and controls. These experiments are highly interdependent, relying upon inferences in one population group for perspective and interpretation in the others. The resulting level of understanding promises to establish the genetic etiology of lupus, spawn new diagnostics, prognostics, and therapeutics which provide therapeutic benefit to this and many related illnesses. RELEVANCE: Systemic lupus erythematosus (SLE) is a debilitating, often life-threatening and sometimes deadly inflammatory disease. Autoimmunity, complement activation, and interferon abnormalities are common themes in pathogenesis. Lupus is hereditary and while progress has clearly been made, the potential for discovery in non-European populations is great. These genes form the basis for understanding pathogenesis making them the foundation upon which are built nevtf diagnostics and therapeutics to combat this disease. Project 1: (Criswell, L and Vyse, T): PROJECT 1 DESCRIPTION (provided by applicant): The major histocompatibility complex (MHC) is the dominant region of association in SLE from European derived subjects. In initial SLEGEN genome wide analyses, 86 SNPs spanning 6.4 Mb reached genome wide Statistical evidence at p<10-6. Combined with a replication cohort, analyses involving 5,278 samples reaches impressive significance levels (p<10-44). Multiple effects within this large region are strongly suggested by these and other data and will be further characterized. The large multiracial collection assembled by SLEGEN is a particular strength for this project. We will use the obvious population differences in the MHC to separate and isolate individual genomic elements containing causative polymorphisms. We have the following specific Aims: Aim 1: Perform a meta-analysis of available high density MHC datasets to more precisely define the locations and extent of genetic effects within the MHC among European-derived populations. Prediction: At least two separate associations in the MHC region will be convincingly established and characterized in the European-derived sample. Aim 2: Define the region and extent of genetic effects across the MHC in populations of non-European origin (i.e. African-Americans, Hispanics and Asians). Prediction: Analysis of additional ethnic groups will facilitate narrowing of associated regions within the MHC due to population substructure differences in MHC haplotypes. Synergies: All of the other Projects will be very important for the success of this Aim. Aim 3: Perform association analyses in subgroups defined by specific SLE disease features. We will examine more homogeneous subgroups as a strategy to further separate the genetic effects within the MHC region, including subsets defined by specific autoantibodies or clinical variables such as nephritis. Prediction;Particular sub-phenotypes will be less genetically heterogeneous and will provide increased statistical power to more precisely define genotype-phenotype correlations and decipher individual effects within the MHC region. RELEVANCE: The MHC represents the most important genetic contribution to SLE for European-derived populations, however prior work has not fully defined the specific causal variants. There is a paucity of data for non- European populations in spite of the excess burden of disease among these groups. A thorough delineation of the MHC contribution to SLE will be crucial to fully understand the role of other causal variants.